US10702614B2 - Radiobacteria for therapy of cancer - Google Patents
Radiobacteria for therapy of cancer Download PDFInfo
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- US10702614B2 US10702614B2 US13/985,087 US201213985087A US10702614B2 US 10702614 B2 US10702614 B2 US 10702614B2 US 201213985087 A US201213985087 A US 201213985087A US 10702614 B2 US10702614 B2 US 10702614B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1203—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules in a form not provided for by groups A61K51/1206 - A61K51/1296, e.g. cells, cell fragments, viruses, virus capsides, ghosts, red blood cells, viral vectors
Definitions
- Pancreatic ductal adenocarcinoma synonymous to pancreatic cancer, is the 4th leading cause of cancer deaths.
- the “silent killer” is characterized by its metastatic behavior (3) before the primary tumor can be detected, resulting in a five-year survival rate of only 4%.
- Current cancer treatments, i.e. surgery, followed by radiation and/or chemotherapy, are ineffective against metastases.
- Gemcitabine and erlotinib FDA-approved drugs for pancreatic cancer treatment, improve median survival by approximately six months in advanced stage patients (1-3), emphasizing the need for new alternative therapies for pancreatic cancer.
- One such approach could be Listeria monocytogenes -based cancer therapy.
- Listeria at provides a therapeutic approach that is particularly useful against metastatic cancer.
- Myeloid derived suppressor cells are normally a major problem in cancer vaccination because they strongly suppress T cell and natural killer (NK) cell responses and promote angiogenesis (4-10), resulting in the development of metastases.
- NK natural killer
- angiogenesis 4-10
- ROS reactive oxygen species
- CTL cytotoxic T lymphocytes
- Radiolabeled small molecules, monoclonal antibodies, peptides and other tumor-targeting vehicles 13
- the radioactive particles emitted by the radionuclides physically destroy the cancerous cells and such therapies are not subject to multidrug resistance mechanisms.
- a radiolabeled tumor specific antibodies AB
- radioimmunotherapy of pancreatic cancer has shown very modest results both pre-clinically (14-16) and in cancer patients with unresectable liver metastases (17). New choices of targeting vehicles are needed to make targeted radionuclide therapy successful in treatment of pancreatic cancer.
- the present invention addresses the need for new targeted cancer therapies by providing “radiobacteria”, including radiolisteria, to treat tumors, including inoperable tumors.
- a method of treating a tumor in a subject, or reducing or preventing metastasis of a tumor in a subject comprising administering to the subject an amount of a bacteria labelled with, or comprising, one or more radionuclides so as to treat the tumor in the subject, or so as to reduce or prevent metastasis of the tumor in the subject.
- a composition comprising an amount of bacteria labelled with, or comprising, one or more radionuclides.
- a pharmaceutical composition comprising an amount of bacteria labelled with, or comprising, one or more radionuclides and a pharmaceutically acceptable carrier.
- Radionuclide-labelled bacteria or bacteria comprising a radionuclide, for the treatment of a tumor or for preventing or reducing metastases of a tumor.
- FIGS. 1A-1B Effect of increasing doses of 188 Re-labeled antibody directed to Listeria upon viability of Listeria .
- Attenuated Listeria monocytogenes (Listeria at ) bacteria were incubated with 60, 120, and 200 ⁇ Ci of 188 Re-Abs (designated as RL-60, RL-120, and RL-200 in the figure), plated on agar (LB only) and next day analyzed for the number of CFU of Listeria at , in order to analyze whether 188 Re kills Listeria at bacteria (A).
- RL-60 RL-120, and RL-200 in the figure
- LB only LB only
- To analyze the stability of RL a similar experiment was performed on LB agar plates with chloroamphenicol (B). All experiments were performed in triplicates and repeated two times. The results were averaged and subjecte
- FIG. 2 Schematic of the testing of radiolabelled Listeria (“radiolisteria”) efficacy in a pancreatic tumor model.
- mice were therapeutically immunized eleven times with the low dose (10 4 CFU) of RL (Listeria at - 188 Re), Listeria at , 188 Re or Saline, and euthanized 21 days later.
- B Number of metastases and
- D From each group a representative is shown of metastases in the portal liver.
- E In the last of the three experiments 188 Re was measured in all tissues of RL-treated mice one day after the last immunization by a gamma counter.
- the p value for comparisons of saline and RL is 0.0030; for listeria and RL is 0.0368; for RL and 188 Re is 0.0126: for saline and listeria is 0.0960; for listeria and 188 Re is 0.5143: and for saline and 188 Re is 0.4318.
- the p value for comparisons of saline and RL is 0.0249; for listeria and RL is 0.0022; for RL and 188 Re is 0.0651.
- the p value for comparisons of saline and RL is 0.0411; for listeria and RL is 0.0163 for RL and 188 Re is 0.1320.
- FIG. 5 Biodistribution of RL in mice with and without tumors.
- FIGS. 6A-6C RL does not destroy T cells or MDSC.
- a method of treating a tumor in a subject, or reducing or preventing metastasis of a tumor in a subject comprising administering to the subject an amount of a bacteria labelled with, or comprising, one or more radionuclides so as to treat the tumor in the subject, or so as to reduce or prevent metastasis of the tumor in the subject.
- the bacteria is Listeria monocytogenes .
- the bacteria is Salmonella thyphimurium. Vibrio cholera, Clostridium , or Bifidobacterium breve .
- the bacteria are labelled with, or comprise, a beta radiation emitter.
- the bacteria are labelled with, or comprise, 188 Re or 32 P.
- the bacteria are labelled with a radionuclide, and are labelled by the radionuclide being bound to an antibody attached to the bacteria.
- the bacteria comprise the one or more radionuclides, and comprise the one or more radionuclides by means of having been cultured in a radionuclide-containing medium.
- the bacteria comprise more than one radionuclide.
- the bacteria labelled with, or comprising, one or more radionuclides are administered systemically to the subject.
- the bacteria labelled with, or comprising, one or more radionuclides are administered locally to the tumor in the subject.
- the bacteria labelled with, or comprising, one or more radionuclides are injected into the tumor in the subject.
- the tumor is a pancreatic tumor.
- the tumor is a tumor of the ovary, uterus, neck, head, breast, prostate, liver, lung, kidney, neurones, glia, colon, testicle, or bladder or is a hepatocellular cancer.
- the tumor is an inoperable tumor.
- the amount of bacteria labelled with, or comprising, the one or more radionuclides provides a radiation dose of 1-500 mCi. In an embodiment the amount of bacteria labelled with, or comprising, the one or more radionuclides provides a radiation dose of 100-200 mCi.
- the bacteria of the inventions described herein are attenuated. In a preferred embodiment, the bacteria of the inventions described herein are isolated or purified.
- composition comprising an amount of bacteria labelled with, or comprising, one or more radionuclides.
- composition comprises a pharmaceutically acceptable carrier.
- a pharmaceutical composition comprising an amount of bacteria labelled with, or comprising, one or more radionuclides and a pharmaceutically acceptable carrier.
- the bacteria are labelled with, or comprise a beta radiation emitter. In an embodiment of the composition or pharmaceutical composition the bacteria are labelled with, or comprise, 188 Re or 32 P. In an embodiment of the composition or pharmaceutical composition the bacteria are labelled with the one or more radionuclides and are labelled by the radionuclide being bound to an antibody attached to the bacteria. In an embodiment of the composition or pharmaceutical composition the bacteria are Listeria . In an embodiment of the composition or pharmaceutical composition the bacteria are Listeria monocytogenes.
- Radionuclide-labelled bacteria or bacteria comprising a radionuclide, for the treatment of a tumor or for preventing or reducing metastases of a tumor.
- the bacteria are Listeria monocytogenes .
- the bacteria are labelled with, or comprise, 188 Re or 32 P.
- the amount of bacteria labelled with, or comprising, the one or more radionuclides provides a radiation dose of 1-500 mCi. In an embodiment the amount of bacteria labelled with, or comprising, the one or more radionuclides provides a radiation dose of 100-200 mCi.
- the invention is particularly useful for types of cancer for which there are practically no effective treatments, like pancreatic cancer (which is almost always detected in metastatic form), ovarian cancer, cancers for which surgery to remove the primary tumor is not an option because of tumor location (as is often the case in head and neck cancers), inoperable hepatocellular carcinoma, and for metastatic disease which is recurrent or refractory to the standard treatments (with non-limiting examples being lung and colon cancers as well as breast cancer).
- pancreatic cancer which is almost always detected in metastatic form
- ovarian cancer cancers for which surgery to remove the primary tumor is not an option because of tumor location (as is often the case in head and neck cancers), inoperable hepatocellular carcinoma, and for metastatic disease which is recurrent or refractory to the standard treatments (with non-limiting examples being lung and colon cancers as well as breast cancer).
- treating means that one or more symptoms of the disease, such as the tumor itself, metastasis thereof, vascularization of the tumor, or other parameters by which the disease is characterized, are reduced, ameliorated, prevented, placed in a state of remission, or maintained in a state of remission.
- Treating also means that one or more hallmarks of the tumor may be eliminated, reduced or prevented by the treatment. Non-limiting examples of such hallmarks include uncontrolled degradation of the basement membrane and proximal extracellular matrix, migration, division, and organization of the endothelial cells into new functioning capillaries, and the persistence of such functioning capillaries.
- reducing or preventing metastasis of a tumor means that any of the symptoms of the disease, such as the metastases, the extent of spread thereof, the vascularization of the metastases or other parameters by which the disease is characterized are reduced, ameliorated, prevented, placed in a state of remission, maintained in a state of remission, or eliminated.
- radiobacteria means bacteria which have been labelled with or comprise (i.e. contain) one or more radionuclide(s).
- radiolisteria means Listeria , preferably Listeria monocytogenes , which have been labelled with or comprise (i.e. contain) one or more radionuclide(s).
- the bacteria or Listeria can be labelled with the radionuclide(s) by, for example, being labeled therewith via a radiolabelled antibody.
- the bacteria or the Listeria are labelled with a polyclonal antibody comprising a radionuclide.
- the bacteria or the Listeria are labelled with a monoclonal antibody comprising a radionuclide.
- the bacteria or the Listeria can comprise the radionuclide(s) by, for example, being grown with the radionuclide(s).
- Listeria can be grown in the presence of such radionuclides which Listeria can then incorporate.
- Listeria are grown in a P-32-containing substrate, eliminating the need for a Listeria -specific antibody.
- Radionuclide as used herein means a radioisotope of an element.
- the choice of the particular radioisotope which the bacteria, such as Listeria comprises, or with which the antibody which attaches to the bacteria, such as Listeria is labeled, will be determined by the type of tumor to be treated and its localization in the body. Two characteristics are important in the choice of a radioisotope—emission range in the tissue and half-life.
- the radioisotope is a beta emitter.
- beta emitters examples include 188-Rhenium (half-life 16.7 hours), 90-Yttrium (half-life 2.7 days), 32-Phosphorous (half-life 14.3 days), 47-Scandium (half-life 3.4 days), 67-Copper (half-life 62 hours), 64-Copper (half-life 13 hours), 77-Arsenic (half-life 38.8 hours), 89-Strontium (half-life 51 days), 105-Rhodium (half-life 35 hours).
- 109-Palladium half-life 13 hours
- 111-Silver half-life 7.5 days
- 131-iodine half-life 8 days
- 177-Lutetium half-life 6.7 days
- 153-Samarium half-life 46.7 hours
- 159-Gadolinium half-life 18.6 hours
- 186-Rhenium half-life 3.7 days
- 166-Holmium half-life 26.8 hours
- 166-Dysprosium half-life 81.6 hours
- 140-Lantanum half-life 40.3 hours
- 194-Irridium half-life 19 hours
- 198-Gold half-life 2.7 days
- 199-Gold half-life 3.1 days
- 188 Re has the additional advantage that it emits ⁇ -rays which can be used for imaging, for example to assess progress of treatment and successful localization of the radiobacteria, such as radiolisteria.
- Longer-lived isotopes such as 90-Yttrium (half-life 2.7 days), 177-Lutetium (half-life 6.7 days) or 131-Iodine (half-life 8 days) may also be used.
- Positron emitters such as 68-Gallium (half-life 68 minutes), 18-Fluorine (half-life 110 minutes), and 61-Copper (half-life 3.4 hours), could also be used to treat abscesses, as well as disseminated diseases.
- radioisotopes which are Auger electron emitters and/or conversion electron emitters could be used; however, such radioisotopes need to be coupled to an antibody type which is internalized by the Listeria.
- Auger electron emitters examples include 67-Gallium (half-life 78 hours), 111-Indium (half-life 2.8 days), 123-Iodine (half-life 13 hours), 125-iodine (half-life 60 days) and 201-Thallium (half life 3 days).
- conversion electron emitters examples include 117m-Tin (half-life 13.6 days).
- radioisotopes that emit both Auger electrons and conversion electrons include 195m-Mercury (half-life 41.6 hours) and 195m-Platinum (half-life 4 days).
- Alpha emitters which have a short emission range in comparison to beta emitters, may be preferable for treatment of tumors or cancers that are disseminated in the body or in the blood.
- alpha emitters include 213-Bismuth (half-life 46 minutes), 223-Radium (half-life 11.3 days), 224-Radium (half-life 3.7 days), 225-Radium (half-life 14.8 days), 225-Actinium (half-life 10 days), 212-Lead (half-life 10.6 hours), 212-Bismuth (half-life 60 minutes), 211-Astatin (half-life 7.2 hours), and 255-Fermium (half-life 20 hours).
- the alpha-emitting radioisotope is 213-Bismuth.
- 213 Bi is currently available in generator form, which allows transportation of this isotope from the source to clinical centers within the United States and abroad.
- an antibody labeled with a radionuclide/radioisotope can be a polyclonal antibody, a monoclonal antibody, or a fragment of a polyclonal antibody, or a fragment of a monoclonal antibody, wherein the fragments retain their binding ability, such as a monovalent or divalent Fab.
- the bacteria such as Listeria
- long range emitters include beta emitters and positron emitters.
- short range emitters include alpha emitters, Auger electron emitters, and conversion electron emitters.
- Positron emitters can also be intermediate range emitters depending on the energy of the positrons.
- the long-range emitter is a beta emitter and the short range emitter is an alpha emitter.
- the beta emitter is 188-Rhenium.
- the alpha emitter is 213-Bismuth.
- Combinations of different radioisotopes can be used, which include an admixture of any of an alpha emitter, a beta emitter, a positron emitter, an Auger electron emitter, and a conversion electron emitter, with physical half-lives from 30 minutes to 100 days.
- the plurality of different radioisotopes is more effective in treating the tumor than a single radioisotope within the plurality of different radioisotopes, where the radiation dose of the single radioisotope is the same as the combined radiation dose of the plurality of different radioisotopes.
- the dose of the radioisotope can vary depending on the localization of the tumor, the severity of the tumor, the method of administration of radiobacteria, such as radiolisteria, (local or systemic) and the decay scheme of the radioisotope.
- a diagnostic scan of the patient with the radiobacteria, such as radiolisteria, with diagnostic radioisotope or with the low activity therapeutic radioisotope can be performed prior to therapy, as is customary in nuclear medicine.
- the dosimetry calculations can be performed using the data from the diagnostic scan.
- Radiobacteria such as radiolisteria
- the former may be preferable against tumors by being less radiotoxic to normal organs.
- the treatment may consist of one dose or several subsequent fractionated doses.
- the subject is a human, and the dose of the radioisotope delivered by way of radiobacteria, such as radiolisteria, is between 1-500 mCi. In different embodiments, the dose of the radioisotope delivered by way of radiobacteria, such as radiolisteria, is between 1-100 mCi, 101-200 mCi, 201-300 mCi, 301-400 mCi, or 401-500 mCi.
- the radiobacteria such as radiolisteria
- therapy delivered herein can be administered over a period of time to the subject alone, or with an adjuvant, or in combination with another anti-cancer agent.
- the anti-cancer agent is a chemotherapeutic.
- Radiobacteria such as radiolisteria
- administration can be accomplished by incorporating the radiobacteria, such as radiolisteria, or a composition comprising such of the present invention into a solution or suspension.
- solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents and other media with the proviso that they are compatible with radiobacteria, such as radiolisteria, viability.
- Buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be added to the extent they are compatible with radiobacteria, such as radiolisteria, viability.
- the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials.
- the radiobacteria such as radiolisteria, may be associated with a pharmaceutically-acceptable carrier which is compatible with radiobacteria viability, thereby comprising a pharmaceutical composition.
- the pharmaceutical composition may comprise the radiobacteria in the pharmaceutically acceptable carrier.
- the pharmaceutical composition may consist essentially of the radiobacteria in a pharmaceutically acceptable carrier.
- the pharmaceutical composition may consist of the radiobacteria in a pharmaceutically acceptable carrier.
- the pharmaceutically-acceptable carrier must be compatible with the radiobacteria, and not unduly deleterious to the subject. The choice of carriers will depend on the method of administration.
- the subject can be a mammal.
- the mammal is a mouse, a rat, a cat, a dog, a horse, a sheep, a cow, a steer, a bull, livestock, a primate, a monkey, or preferably a human.
- Cross-fire is responsible for the therapeutic efficacy of FDA approved radiolabelled antibodies Zevalin® and Bexxar® used for treatment of primary, refractory and recurrent non-Hodgkin lymphoma, and in experimental targeted radionuclide therapies.
- a commercially available polyclonal antibody to Listeria (BD Ditco Listeria O antiserum Poly serotype 1,4; Cat. #223021) was radiolabelled with 188 Re (as in Dadachova E. et al. PNAS 2004, (5)) and 1 ⁇ 10 8 Listeria in 1 mL PBS were incubated either with 40 ⁇ g of unlabeled antibody, or with 60, 120 or 200 ⁇ Ci of 188 Re-antibody for 1 hr at 30° C., supernatant removed, and the 188 Re- Listeria taken up in 1 mL PBS and plated with or without Chloroamphenicol. As seen from the viability data in FIG.
- the Listeria at strain used contains a Listeria chloroamphemicol-resistant plasmid pGG34 while the Listeria at itself is chloroamphenicol sensitive. If the Listeria at is unstable and loses its pGG34 plasmid, it will not grow on chloroamphenicol.
- serial dilutions of RL-60, RL-120, and RL200 as well as of Listeria at were plated on agar with chloroamphenicol. Somewhat lower (but significant) number of colonies was observed with RL-200 (which contained the highest concentration of 188 Re-Ab (20 ⁇ Ci)), compared to Listeria at alone when cultured with chloroamphenicol ( FIG. 1B ).
- RL-200 which contained the highest concentration of 188 Re-Ab (20 ⁇ Ci)
- mice were challenged with 2 ⁇ 10 6 Panc-02 tumor cells in the mammary fat pad on day 0. This resulted in a small primary tumor in the mammary fat pad palpable on 5-7 days, and metastases were found predominantly in the portal liver, accompanied with a strong production of ascites within 21 days. Three days after tumor cell injection, mice were immunized every day with 10 4 CFU of RL/500 ⁇ l Saline (Group I).
- liver functions such as aspartate transaminase (AST) and alanine transaminase (ALT), one week after the last of eleven immunizations with RL, Listeria at , free 188 Re, or Saline. No pathological damage was observed by RL, 188 Re or Listeria at (Table 1), and liver functions were not altered by RL, 188 Re, or Listeria (Table 2).
- RL is highly pertinent for application in patients with pancreatic, kidney and liver cancers, as well as other cancers as well.
- mice Normal female C57Bl/6 mice aged 3 months were obtained from Charles River and maintained in the animal husbandry facility Albert Einstein College of Medicine according to the Association and Accreditation of Laboratory Animal Care (AACAC) guidelines. All mice were kept under Bsl-2 condition as required for Listeria at vaccinations.
- the Panc-02 cell line was kindly provided by Chandan Guha (Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, N.Y.).
- the Panc-02 cells were cultured in McCoy's medium supplemented with 10% FBS, Glutamine (2 mM), nonessential amino acids, sodium pyruvate (1 mM), Hepes (10 mM), and Pen/Strep (100 U/ml).
- Listeria at -based vaccine In this study, a highly attenuated Listeria monocytogenes (Listeria at ) was used as the vaccine, as described previously (19).
- the Listeria at plasmid pGG-34 is chloroamphenicol-sensitive, and expresses the positive regulatory factor A (prfA) as well as Listeriolysin O (LLO), required to escape the vacuole after infection (28).
- the coding region for the C-terminal part of the LLO (cytolytic domain that binds cholesterol in the membranes) protein in the plasmid has been deleted, but Listeria at is still able to escape the vacuole upon infection (30).
- 188 Rhenium and anti-Listeria antibodies 188 Re was obtained from 188 W/ 188 Re radionuclide generator (Oak Ridge National Laboratory, TN).
- the commercially available polyclonal antibody to Listeria IgG1 isotype, BD Difco Listeria O antiserum Poly serotype 1,4; Cat. #223021; This anti-serum has high avidity and affinity for Listeria at bacteria and does not dissociate (worldwideweb.bd.com/ds/productCenter/223021.asp)
- the isotype matching control Ab to account for any possible non-specific binding of the IgG to the Listeria at has been radiolabeled with 188 Re as described previously (18).
- Tumor challenge and immunizations were performed as described previously with minor modifications (11). Briefly, Panc-02 tumor cells (2 ⁇ 10 6 ) were injected into the mammary fat pad on day 0. In the Panc-02 model, the primary tumor extends to the chest cavity lining which is palpable 5-7 days after tumor cell injection, but primary tumors stayed relatively small, while metastases predominantly develop in the portal liver, resulting in the production of ascites in the peritoneal cavity within approximately 20 days.
- Immune cells from blood and primary tumors from individual mice were isolated as described previously (32,33). Briefly, red blood cells were lysed according to standard protocols, and the remaining leukocyte population was used for analysis. Single cell suspensions were obtained from primary tumors using GentleMacs combined with a mild treatment of the cells using Collagenase, Dispase, and DNAse I, according the manufacturers instructions (Miltenyi Biotec Inc, Auburn, Calif.).
- Fc blocker anti-CD16
- CD4 and CD8 T cells anti-CD8 antibodies were used.
- cytofix/cytoperm kit from Pharmingen according manufacturers instructions, and antibodies to IFN ⁇ were used.
- anti-CD11b and anti-Gr1 antibodies were used. Appropriate isotype controls were used for each sample.
- Isolation of Listeria from metastases, tumors and normal tissue Mice with Panc-02 metastases and tumors were immunized once with a high dose Listeria at (0.5 ⁇ 10 7 CFU), or eleven times with a low dose (10 4 CFU) and euthanized at various time points as indicated in the text. Metastases, tumors and normal tissues were dissected and homogenized, plated on agar, and counted for Listeria at colonies the next day. The number of Listeria at CFU was calculated per gram tissue.
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Abstract
Description
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